Conceptual models of breast cancer progression. (a) Sequential acquisition of molecular alterations with selection of advantageous 'hits' and corresponding morphologic progression (modified from Burstein and coworkers ). Individual 'hits' are depicted with small 'lightening bolts'. (b) Hyperplasia results in shortening telomeres, rapidly increasing genetic instability during 'telomere crisis', and relative stability after telomerase reactivation (modified from Chin and coworkers ). Individual cells reactivating telomerase and with a 'fit' genetic profile give rise to the carcinoma in situ (DCIS) and then the invasive carcinoma. (c) Genetically stable precancer stem cells are initiated via oncogene activation with divergent behavior programmed via epigenetic encoding and possible but not required genetic content changes. Intermediate morphologic and molecular events are not required for progression. These cells give rise to the DCIS and have an innate latency to invasive carcinoma and an innate metastatic potential.